Fibrinogen is a soluble glycoprotein that is synthesized in liver hepatocytes and megakaryocytes. Fibrinogen is useful in forming bridges between platelets and is the precursor to fibrin, a protein involved in the clotting of blood. Elevated fibrinogen levels have been linked to cardiovascular diseases and conditions and other diseases as discussed herein.
Exendins are peptides that were first isolated from the salivary secretions of the Gila monster, a lizard found in Arizona, and the Mexican Beaded Lizard. Exendin-3 (SEQ ID NO: 1) is present in the salivary secretions of Heloderma horridum, and exendin-4 (SEQ ID NO: 2) is present in the salivary secretions of Heloderma suspectum (Eng, J., et al., J. Biol. Chem., 265:20259-62, 1990; Eng., J., et al., J. Biol. Chem., 267:7402-05, 1992).
Glucagon-like peptide 1 (GLP-1) (SEQ ID NO: 3) is a product of processing of proglucagon. Circulating biologically active GLP-1 is found in several forms including the GLP-1(7-36) amide and GLP-1(7-37) forms. GLP-1 is secreted from gut endocrine cells in response to nutrient ingestion and plays multiple roles in metabolic homeostasis following nutrient absorption. An important locus for regulation of GLP-1 biological activity is the N-terminal degradation of the peptide by Dipeptidyl Peptidase-4 (DPP-4) -mediated cleavage at position 2 alanine of GLP-1(7-37). By convention in the art, the sequence numbering of GLP-1 and analogs customarily begins with residue 7, corresponding to the N-terminal residue of GLP-1(7-37). Unless indicated otherwise, this convention is followed herein.
Disclosed herein are therapeutics and methods of use thereof for decreasing the concentration of fibrinogen in a subject.